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Title: Maternal programming of neural gene methylation and transcription
Author: Irwin, Rachelle E.
ISNI:       0000 0004 5993 2857
Awarding Body: Ulster University
Current Institution: Ulster University
Date of Award: 2016
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DNA methylation is an integral mechanism for regulating a wide variety of biological processes, including those vital for normal growth and development. This biochemical modification occurs predominantly at cytosine bases, patterns of which are established in early development and maintained throughout the lifetime of the organism. Specific genes, such as the imprinted genes, are dependent upon DNA methylation for their regulation and many inherit precise methylation patterns from either parent during embryonic development. Misregulation of this inheritance or lack of maintenance of inherited DNA methylation patterns has been associated with disease aetiologies. The research in this thesis presents two novel classes of genes, namely testis and brain-specific genes, which inherit methylation from the mother, and behave similarly to imprinted genes in that these loci retain inherited methylation throughout preimplantation. The establishment of methylation at these genes is controlled by DNMT3L in oocytes, and the maintenance of this inherited methylation is ensured by both DNMTI and DNMT3A/B enzymes in the blastocyst. Contrary to imprinted genes, the novel gene classes presented in this thesis gain methylation post-implantation on the paternal allele, and thus are deemed transiently-imprinted loci. The testis-specific genes exhibited methylation at the promoter region which upon knockout of the maintenance methyltransferases or usmg pharmacological inhibitors of methylation resulted in transcriptional activation of these genes. Contrarily, the brain-specific genes were characteristically devoid of methylation at the promoter region and instead exhibited intragenic methylation, which by using similar genetic and pharmacological approaches resulted in transcriptional downregulation of these genes, highlighting an additional role of DNA methylation in aiding gene expression. Upon further examination, these genes appeared to be highly methylated in brain tissue where they are heavily transcribed, and the majority of methylation appeared to be 5- hydroxymethylcytosine, acquired during postnatal brain development which was not inherited from the oocyte. DNA methylation patterns are established during development however these are not unalterable to change under environmental influence, such as the maternal diet. In this thesis, we carried out a follow-up study to a previous randomised control trial; the F ASSTT study, revealing that folic acid supplementation of the maternal diet in late gestation can result in sex-specific alterations to imprinted genes, and also changes in methylation to specific sites of transiently-imprinted loci. Although women are universally recommended to supplement their diet with folic acid during the first trimester, there remains no clinical recommendation as to whether this supplementation should be continued into late gestation, as the effects on several genes are currently unknown. This thesis presents new insights into the programming of transiently-imprinted genes during development and the effects of folic acid during late gestation in the offspring.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available